Since we have discovered that the single dose morphine pretreatment of mice to enhance naloxone sensitivity is in part due to increased penetration of naloxone into the brain, we have postulated that this type of effect is dependent upon the physical chemical characteristics of the naloxone. Thus, we are extending this concept to see whether agonists such as etorphine which also rapidly penetrates the brain will be enhanced by morphine pretreatment. Preliminary experiments seem to support this contention even though we find that it is difficult to directly demonstrate enhanced sensitivity to etorphine. Etorphine brain levels are higher in morphine pretreated mice. Now the question whether other analgesics will be sensitized by the morphine pretreatment. These experiments require the determinations of ED50 and pA values for antagonists so that a lot of time and effort is required. Extension of these effects to tolerant animals will be extensively tested. The reason is that we have found that morphine pellet mice tolerant to morphine are not cross tolerant to etorphine. Etorphine tolerant mice are tolerant to morphine. Thus this one way cross tolerance phenomenon will be studied further to recomfirm the finding. Further, other combinations of narcotic analgesics will be tested to see if one way cross tolerance exists to other agents. We recognize that some of the ideas we have are contrary to classical dogma and expected evidence; nevertheless, we feel these one way cross tolerance experiments may hold the key to another way to study the mechanisms of tolerance. Such an approach would indeed be innovative.